Investigation of cerebellar involvement in AUD

AUD 中小脑受累的调查

• 批准号: 10502668
• 负责人: JOHN E DESMOND
• 金额: $ 59.87万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10502668
• 关键词: Address; Alcoholism; Alcohols; Animals; Anodes; Behavioral; Blinking; Brain; Brain Stem; Brain region; Cathodes; Cell Nucleus; Cerebellar Diseases; Cerebellum; Corpus striatum structure; Coupling; Data; Disinhibition; Event; Functional Magnetic Resonance Imaging; Functional disorder; Human; Individual; Intervention; Investigation; Lead; Link; Measures; Motor Cortex; Nature; Neurons; Nucleus Accumbens; Outcome; Output; Participant; Pathway interactions; Patients; Performance; Prosencephalon; Psychophysiology; Reflex action; Relapse; Rest; Rewards; Signal Transduction; Source; Stimulus; Structure; System; Therapeutic; Ventral Tegmental Area; addiction; alcohol craving; alcohol cue; alcohol effect; alcohol response; alcohol use disorder; base; classical conditioning; conditioned place preference; conditioning; craving; cue reactivity; disorder control; drinking; expectation; eyeblink conditioning; financial incentive; hemodynamics; motor control; neuroregulation; neurotransmission; response; reward processing

Recent animal studies have provided new evidence that the cerebellum may have a stronger link to the reward system of the brain than was previously recognized. Direct projections from cerebellar deep nuclei (DN) to the ventral tegmental area (VTA) have been identified, and stimulation of these cerebellar afferents to the VTA was found to be rewarding. Such findings raise the possibility that cerebellar dysfunction could contribute substantially to addiction via a cerebellar influence over VTA. Consistent with animal findings, we have found in human fMRI preliminary data strong cerebellar and VTA activation in response to alcohol cues relative to non- alcohol stimuli in patients with alcohol use disorder (AUD) compared to controls, and close coupling observed between DN and VTA activation. Studying AUD and control participants, this project will address three important questions. The first is: What is the nature of cerebellar input to the VTA, and how is it perturbed in AUD? A number of investigations have suggested that when a stimulus is presented, the cerebellum generates a prediction of events that will follow based on prior associative learning, and then compares predicted and actual outcomes to generate a prediction error. We hypothesize that these functions are disrupted in AUD. Our preliminary data show that when an expected stimulus does not occur, a strong prediction error signal in the form of increased functional connectivity (FC) between cerebellum and its projection target is observed, and we found an analogous increase in DN-VTA FC, that was abnormal in AUD patients, when alcohol pictures were presented. In Aim 1, using fMRI and a monetary incentive task, we will investigate if DN-VTA FC reflects reward prediction and/or positive or negative reward prediction error. The second question is: Is the amount of activation in brain reward centers that is elicited by alcohol stimuli related to the amount of dysfunction in the cerebellum? In Aim 2 we will investigate 2 measures of cerebellar integrity to determine their relationship with the magnitude of alcohol cue related activation in cerebellar, VTA, and other reward structures, and with DN- VTA FC: (1) The timing of the undershoot of the cerebellar hemodynamic response function (HRF), which has been found to be correlated with number of lifetime drinks; and (2) classical eyeblink conditioning, for which the cerebellum is necessary. The third question is: Can abnormal cerebellar activation and FC, as well as alcohol craving, be reduced by non-invasive cerebellar stimulation? In Aim 3, Using fMRI combined with cerebellar transcranial direct current stimulation (tDCS) during a cue reactivity task, we hypothesize that in AUD participants cerebellar and VTA activation will be reduced, DN-VTA FC will be normalized, and alcohol craving will be reduced. We will examine, using both resting state fMRI and psychophysiological interaction analysis, the effects of tDCS on FC among important structures of the reward system as well as on DN-VTA FC. These investigations will lead to a better understanding of the involvement of the cerebellum in AUD, as well as the therapeutic potential of cerebellar modulation.

最近的动物研究提供了新的证据，表明小脑可能与奖励有更强的联系 大脑系统比以前认识到的系统。从小脑深核（DN）到直接投影 已经确定了腹侧对盖区域（VTA），对这些小脑的刺激是VTA的 发现很有意义。这样的发现增加了小脑功能障碍可能导致的可能性 通过小脑对VTA的影响，基本上是对成瘾的。与动物发现一致，我们在 人fMRI初步数据强的小脑和VTA激活，响应于酒精提示 与对照组相比，酒精使用障碍患者（AUD）的酒精刺激以及观察到的紧密耦合 在DN和VTA激活之间。研究AUD和控制参与者，该项目将解决三个 重要问题。第一个是：小脑输入对VTA的本质是什么？ 澳元？许多调查表明，当提出刺激时，小脑会产生 根据先前的关联学习将遵循的事件的预测，然后比较预测和 实际结果生成预测错误。我们假设这些功能在AUD中被破坏。我们的 初步数据表明，当未发生预期刺激时，在 观察到小脑及其投影目标之间功能连通性（FC）的增加形式，并且 我们发现DN-VTA FC的同样增加，当时AUD患者异常，当时酒精摄影 被提出。在AIM 1中，使用fMRI和一项货币激励任务，我们将研究DN-VTA FC是否反映 奖励预测和/或正面或负面奖励预测错误。第二个问题是：数量是 大脑奖励中心的激活与酒精刺激引起的与功能障碍量有关的激活 小脑？在AIM 2中，我们将研究2个小脑完整性的措施，以确定它们与 小脑，VTA和其他奖励结构中酒精提示相关的激活的大小以及DN- VTA FC：（1）Cerebellar血液动力学反应函数（HRF）的时间安排 发现与终身饮料数量相关； （2）经典的眉毛条件，为此 小脑是必要的。第三个问题是：小脑异常激活和FC可以以及酒精 渴望，通过非侵入性小脑刺激减少？在AIM 3中，使用fMRI与小脑结合 在提示反应性任务中，我们假设在AUD中，经颅直流电流刺激（TDC） 参与者小脑和VTA激活将减少，DN-VTA FC将被归一化，并渴望酒精 将减少。我们将使用静止状态fMRI和心理生理相互作用分析检查， TDC对奖励系统重要结构以及DN-VTA FC的影响。这些 调查将使人们更好地了解小脑参与AUD的参与以及 小脑调节的治疗潜力。